THE 6 TH NATIONAL SCIENTIFIC CONFERENCE ON HIV/AIDS MONITORING OF HIV DRUG RESISTANCE IN CHILDREN...

THE 6TH NATIONAL SCIENTIFIC CONFERENCE ON HIV/AIDS

MONITORING OF HIV DRUG RESISTANCE IN CHILDREN RECEIVING

FIRST LINE ANTIRETROVIRAL THERAPY AT TWO CHILDREN

HOSPITALS NHI ĐỒNG 1 AND NHI ĐỒNG 2 IN HO CHI MINH CITY,VIETNAM

Ton Tran(1), Anh Q. Luong(1), Khanh Thu H. Huynh(1), Ngoc Thao T. Do(1), Nghia V. Khuu(1), Thinh X. Vu(1), Khanh H. Truong(2), Quy T. Du(2), Kim Thoa P. Le(2), Viet C.

Do(3), An T. Vu(3), Thanh Thuy T. Le(3), Xuan Lien T. Truong(1).(1)Pasteur Institute, Ho Chi Minh City, (2)Nhi Dong 1 hospital, Ho Chi Minh City, (3)

Nhi Dong 2 hospital, Ho Chi Minh City

The 6th National Scientific Conference on HIV/AIDS

Outline

1. Background

2. Objectives

3. Methods

4. Results & Discussions

5. Conclusions

6. Recommendations


INTRODUCTION

The biggest barrier in treatment for

HIV/AIDS patients is ARV drug

resistance problem

1. Background


INTRODUCTION


Early detection of HIVDR and changing

appropriate ARV regimens helps prevent:

•Accumulation of resistance mutations

•Poor response or non-response to HAART

•Serious clinical events and mortality

•Prolonged viremia and risk of transmission

INTRODUCTION


In Vietnam:

On adult patients

(1) Early Warning Indicator of HIVDR (EWI): từ 2010

(2) Mornitoring of HIVDR: 2009 - 2012

(3) HIVDR threshold survey: from 2011.

(4) Cross-sectional studies on HIVDR on ARV- naive patients, ART patients, . . .

Lack of HIVDR data on pediatrics

INTRODUCTION


2. Objectives1. Identify specific HIVDR mutations and mutation

patterns in populations at initiation of first-line ART2. Estimate the proportion of the ART site population

achieving HIVDR prevention, as measured by viral load suppression, in populations after one year of first-line ART

3. Identify specific HIVDR mutations and mutation patterns in populations not achieving prevention of HIVDR on first-line ART.

4. Identify programmatic factors potentially associated with the prevention (or non-prevention) of HIVDR.


METHOD

1- Study design: cohort study

2- Study subjects: HIV/AIDS children at initiation of

first line anti-retroviral therapy at two children hospitals

Nhi Đồng 1 and Nhi Đồng 2 in Ho Chi Minh city

3- Duration: 12/2011 – 03/2014

3. Methods


METHOD


Exclusion criteria:•Individuals enrolled in a clinical trial or clinical research study (either at the monitoring site or another location).•Individuals who are part of an observational cohort for whom more follow-up efforts are made than for other ART patients treated at the site (Patients enrolled in an observational cohort for whom no additional follow-up procedures are included may be eligible).•Individuals restarting ART, who have previously started and stopped ART at the sentinel survey site.•Individuals transferring in from another paediatric ART site who are at the time of transfer currently taking a three- or four-drug first-line ART regimen .

METHOD


PROCEDUREEnrollment criteria Consultant

Agree Disagree

Cont. as normalData + sample

HIV VL testingHIVDR genotyping

HIVDR genotyping Cont. as normal

≥1000 cps/ml <1000 cps/ml

Monitoring as normal & HIVDR analysis

Data entry and analysis for baseline

Monitoring as normal

Data + sample for HIV VL

Stop 1st line regimens or after 12 months


Testing at HIV/AIDS laboratory of Pasteur Institute: -HIV-1 Viral load by Real time PCR (Generic HIV Charge Virale of Biocentric – France, LOD: 250 cps/mL) -HIVDR genotyping:

• Sequencing of Pol gen (1800 bp) => coding for proteins which are targets of NRTIs, NNRTIs & PIs being used in Vietnam.

• Sequence analysis by DNAStar Lasergene 12 Core Suite

• Sequence interpretation with HIVdb program of Stanford HIV drug resistance database (USA).


RESULTS

Baseline Characteristics

• 136 eligible children consecutively initiating first line ART were enrolled; male/female: 69/67

• 31,62 % were HIV diagnosed before 18 months of age. 72,06% were detected after 18-month old.

• 75,21 % of children >18 months of age, 39,67 % of children >5 years old at ART initation

4. Results & Discussions


• 6/136 of patients‘mothers joined in PMTCT program, including 3 ones were HIV detected at labor

• Number of children having ARV in PMTCT program was 11/136 (8,09%)

• 47/136 (34,55%) had advanced disease – WHO clinical stages III and IV at ART initation

• 65/136 (47,79%) were severely immunocompromised

(LT CD4 <15%) at ART initation

RESULTS


• 100% had HIV VL > 3log cps/ml, of whom 81,62% had HIV VL > 5log cps/ml at ART initation

• 32 (37,21%) had OIs, of whom 58,54% had tuberculosis at ART initation.

• 5,15 % (7/136) had HBsAg (+), 3,68% (5/136) had anti HCV (+) & 2,20% (3/136) had Cryptococcus Antigen (+).

• 134/136 (98,53%) had HIV-1 subtype CRF01-AE


7 (5%) were dead, 8 (6%) were loss-follow up

Most of 121 children continued to be monitored had clinical and immunological status well changed (p< 0,001)

•97,52% (119/121) had WHO clinical stage I after 12 months of ART

•92,56% (112/121) had LT CD4 ≥ 15%

87,6% of patients had suppressed HIV RNA at 12 months after ART initation with HIV VL <3log cps/mL

Outcomes at 12 monthsRESULTS


Number of children

with DR mutations

Prevalence

%Mutation

NRTI 2 1,47 T215A

NNRTI 1 0,74 N348I

PI 4 2,94M46L,

K20I, T74S

Total 7 5,15

HIVDR at ART initiation


Number of

children with DR

mutations

Prevalence

%Mutation

NRTI 7 5.15 T69N, V75L

NNRTI 2 1.47 V179D/E

Both NRTI &

NNRTI1 0.74 N348I

PI 5 3.68 L10I/V, L33I

Total 15 11.04

Mutation associated with resistance


Of 9 of children with TB and TB treatment in parallel with ART, there were 5 cases (55.56%) had DRMs => 6 times compared with the proportion of non-TB patients B had DRMs (p = 0.01)

HIVDR outcomes after 12 months of ART

Number of children had DR mutations %

NRTIs 9 7,44Dual resistance to both NRTIs

& NNRTIs6 4,96

PIs 0 0

RESULTS


Drug Resistance Mutations12/15 samples with VL ≥3log cps/mL

RESULTS


DRM InterpretationResistance to NRTIs

At ART initiation: T215A, T69N và V75L. T215A: low-level resistance to D4T & AZT,

potential low-level resistance to ABC & DDI (ART naive).

T69N: potential low-level resistance to DDI V75L: potential low-level resistance to D4T &

DDI. None of TAMs were recorded.


DRM InterpretationAfter 12months of ART: D67N, K70R, L74V, V75M, V75T,

Y115F, Q151M, M184V, T215F, T215S & T215N. M184V: detected in 6/12 cases (50%), selected by 3TC and reduces susceptibility to this drugs >1000-fold. It is also selected by, and causes low-level resistance to, ABC and ddI

V75M: high-level resistance to d4T and medium-level resistance to ddI.

Q151M: intermediate/high-level resistance to AZT, ddI, d4T and ABC and low-level resistance to TDF, 3TC and FTC. In combination with mutations at the associated positions 62, 75, 77, and 116, Q151M confers high-level resistance to AZT, ddI, d4T and ABC and intermediate-level resistance to TDF, 3TC and FTC. PED1-025 had Q151M, F77L and F116FY.

TAMs: D67N, K70R, T215F, K219Q. PED2-003 had 3 TAMs (D67N, K70R and K219Q)


Resistance to NNRTIsLow genetic barrier, 1 primary mutation reduced susceptibility to the relevant NNRTIs. At ART initiation:

Primary mutation : N348I low-level resistance to NVP, potential low-level resistance to EFV and AZT, D4T.

V179D/E potential low-level resistance to all of 4 NNRTIs

After 12months of ART: 5/9 of primary mutation to NNRTIs were detected: K101E, K103N, Y181V, Y188L and G190A => multi DR with all regimens of NNRTIs


Resistance to PIs

At ART initiation: Major mutation: M46L: nonpolymorphic PI-selected mutations that reduce susceptibility to IDV, NFV, FPV, LPV and ATV when present with other mutations. M46L also reduces susceptibility to TPV. Minor mutations: K20I is a PI-selected mutation that appears to reduce NFV susceptibility; T74S is a polymorphic mutation weakly selected by most PIs and associated with low-level resistance to NFV. L10I/V, L33I not effect on PI susceptibility


Resistance to PIsAfter 12 months of ART:

Major mutation: not detected. Minor mutation: only L10I/V recorded not effect on PI susceptibility


• Most of HIV-infected children were detected late with high viral load, compromised immunity, late clinical stage due to accessing testing, care and treatment services late.

Need more interventions to increase accessibility to care - treatment programs for children born to HIV infected mothers.

CONCLUSION (1)

5. Conclusions & Recommendations (1)


• Low level of HIVDR were observed among children after 12 months of ART.

• HIVDR associated mutations related to multi - drug resistance were recorded and dual class resistance, including combined NRTI and NNRTI, was present after only 12 months of ART

Continue to monitor HIVDR in children to provide the information needed to contribute to the HIV treatment guidelines for children in the actual conditions of Vietnam.

CONCLUSION (2)



• Having TB and TB treatment in parallel with ART seemed to relate to the emergence of HIV drug resistance

Need to be considered in the National ARV treatment guidelines

CONCLUSION (3)



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